Process for preparing 1,2,3,8,9,9a-hexahydro-5,6-dialkoxy-1-alkyl-benzo(d,e)quinolin-7-ore compounds

ABSTRACT

1,2,3,8,9,9a-Hexahydro-5,6-di-lower alkoxy-1-lower alkylbenzo(d, e)quinolin-7-ones, prepared from the corresponding 1,2,3,4tetrahydro-6,7-di-lower alkoxy-2-lower alkyl-isoquinoline-1propionic acids or lower alkyl esters thereof, are described. The end products are useful as intermediates for alkaloids of the nuciferine type.

United States Patent Bernauer et al. July 22, 1975 [54} PROCESS FORPREPARING 3,346,581 10/1967 Gootjes 260/289 Rl,2,3,8,9,9A-HEXAHYDRO-5,6-DIALKOXY- l ALKYL BENZO[DE]QUINOLIN 7 OREFOREIGN PATENTS OR APPLICATIONS COMPOUNDS l,O54,095 1/1964 UnitedKingdom .i 260/289 R [75] Inventors: Karl Bernauer, Allschwil', JanosOTHER PUBLICA'HONS Borgulya; Fernand Schneider, both of Basel, all ofSwitzerland Morrison et al., J. Org. Chem, Vol. 29, I964, pp, [73]Assignee: l-loffmann-La Roche Inc., Nutley, 2486.248?" PrimaryExaminer-Donald G. Daus [22] Flled' 1973 Assistant Examiner-Mary C.Vaughn [21] Appl. No.: 321,069 Attorney, Agent, or Firm-Samuel L. Welt;Bernard S.

Related US. Application Data Leon; wllllam [Sgro [62] Division of Ser.No. 57,348, July 22, 1970,

57 ABSTRACT gn Application Priority Datal,2,3,8,9,9a-Hexahydro-5,6-di-1ower alkoxy-l-lower Aug 19. 1969Switzerland 12532/69 alkylbenzo[d,elquinolin-l-ones, prepared from thecorresponding l,2,3,4-tetrahydro-6,7-di-l0wer alkoxy [52] US. Cl.260/289 R; 424/258 2-lower alkyl-isoquinoline-l-propionic acids or lower[51] Int. Cl C07d 33/46 alkyl esters thereof, are described. The endproducts [58] Field of Search 260/289 R are useful as intermediates foralkaloids of the nuciferine type. [56] References Cited UNITED STATESPATENTS D'awmgs 3,341,528 9/l967 Shave] et al 260/289 R PROCESS FORPREPARING l,2,3,8,9,9A-l-IEXAHYDRO-5,G-DIALKOXY- lALKYL-BENZO[D,E]QUINOLIN-7-ORE COMPOUNDS This is a division ofapplication Ser. No. 57,348 filed July 22, I970, now abandoned.

BRIEF SUMMARY OF THE INVENTION The invention relates tohexahydrobenzoquinoli' nones of the formula wherein R R and R are loweralkyl, and acid addition salts thereof.

As used herein, the term lower alkyl denotes a hydrocarbon of l7 carbonatoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,tert. butyl, pentyl, hexyl and heptyl. Preferred lower alkyl moietiesare those of l-4 carbon atoms. A particularly preferred compound is thecompound of formula l, wherein R R and R are methyl, i.e.,l,2,3,8,9,9ahexahydro-5,6-dimethoxy-l-methyl-benzo{d,e]quinolin-7-one,and its acid addition salts.

The compounds of formula I and their acid addition salts are useful asintermediates for the syntheses of alkaloids. They can, for example, beconverted into alkaloids of the nuciferine type, which possesshypotensive activity. Thus, for example, nuciferoline can be obtainedfroml,2,3,8,9,9a-hexahydro-5,6-dimethoxy-lmethyl-benzo[d,e]quinolin-7-one byreaction with methyl ethynyl ketone.

The compounds of formula I and their acid addition salts can be obtainedby cyclizing a compound of the formula wherein R R and R are aspreviously described and R is hydrogen or lower alkyl,

or salt thereof by treatment with sulfuric acid containing free sulfurtrioxide at a temperature in the range of about 65C. to about 85C., bytreatment with hydrogen fluoride at a temperature in the range of about-l to about +50C., or by treatment with polyphosphoric acid at atemperature in the range of about 60 to about 100C. Optionally, a baseobtained can thereafter be converted to an acid addition salt.

In a preferred embodiment, there is employed as the starting material acompound of formula I] or an acid addition salt thereof wherein R., Rand R each are methyl.

When utilizing sulfuric acid containing free sulfur trioxide (oleum asthe cyclizing agent, it has been found to be advantageous to employ asulfuric acid with a content of about l0-30 wt.%, preferably about l-20wt.%. of sulfur trioxide. Under such circumstances, the cyclization iscarried out at a temperature in the range of about 65 to about 85C.,preferably at about 80C. In carrying out this cyclization, there can beused, per

part by weight of starting material, about 2-l 5 parts by weight,preferably about l0 parts by weight, of sulfuric acid containing freesulfur trioxide. Depending on the reaction temperature utilized, thereaction can be completed in about 3 to 10 minutes. A preferred reactiontime is at about 5 minutes.

The reaction thus obtained can then be diluted with water, made alkalineand extracted, for example, with methylene chloride. After evaporationof the methylene chloride, the desired end product remains.

In the cyclization with hydrogen fluoride, anhydrous liquid hydrogenfluoride is preferably utilized. In this case, the cyclization isundertaken at a temperature in the range of about -l0 to about +50C.,preferably in the range of about 0C. to about 20C. It is convenient toconduct the reaction at room temperature. At temperatures above theboiling point of hydrogen fluoride, the reaction is expedientlyconducted in a closed vessel. Particularly suitable as reaction vesselsare those made of polyethylene. In carrying out this cyclization, therecan be used, per part by weight of starting material, about 3-20 partsby weight, preferably about 10 parts by weight, of hydrogen fluoride.Depending on the reaction temperature utilized, the reaction iscompleted in a few hours to a few weeks. In the preferred temperaturerange of about 0 to about 20C., the reaction time is generally about 10to about 100 hours. The desired reaction product can be obtained bydiluting the reaction mixture with water, making it alkaline andextracting it, for example, with methylene chloride.

When polyphosphoric acid is used as the cyclizing agent, the cyclizationis effected at a temperature in the range of about 60 to about l00C.,preferably in the range of about to about 90C. It has been found to beparticularly preferred to carry out the cyclization at about C. Incarrying out this cyclization, there can be used, per part by weight ofstarting material, about 4-15 parts by weight, preferably about 10 partsbe weight of polyphosphoric acid. Depending on the reaction temperatureutilized, the cyclization is completed in about 5 to l0 minutes. Whenthe reaction temperature is about 80C., the cyclization is completed inabout 8 minutes. The desired reaction product can be obtained bydiluting the reaction mixture with water, making it alkaline andextracting it, for example, with methylene chloride.

Bases of formula I can be converted in a known manner into acid additionsalts with inorganic or organic acids, for example, hydrochloric acid,sulfuric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acidor the like.

The following examples further illustrate the invention. Temperatures,unless otherwise stated, are expressed in degrees Centigrade.

EXAMPLE 1 Preparation of 1,2,3 ,8 ,9,9a-hexahydro-5 ,6- dimethoxyl-methylbenzo[ d,e]quinolin-7-one 390 g. of concentrated sulfuric acid(about 96%) and 100 g. of fuming sulfuric acid (about 60% S are mixed atroom temperature and 124.2 g. of l,2,3,4- tetrahydro-6,7-dimethoxy-Z-methyl-isoquinoline-l-propionic acid hydrochloride are addedportionwise with stirring. The reaction mixture is heated to 80 for 5minutes and subsequently poured onto 3 kg. of ice and 6 l. of H 0. Theaqueous solution is made alkaline with 1200 ml. of caustic soda (28%)and extracted with three 3 1. portions of methylene chloride. Theorganic phase is dried over sodium sulfate and concentrated in a rotaryevaporator (pressure: 16 cm Hg, bath temperature: 50'). 106 g. of theoily product obtained are dissolved in 200 ml. of ether and crystallizedat dry-ice temperature. After filtration and air-drying, l,2,3,89,9a-hexahydro-5 ,-dimethoxyl -methyl-benzo[d,e1- quinolin-7-one isobtained in crystalline form having a melting point of 72-75.

EXAMPLE 2 Preparation of l,2,3,8,9.9a-hexahydro-5 ,6- dimethoxyl-methylbenzo[d,e ]quinolin-7-one The reaction hereinafter described iscarried out under an extractor. Hands are to be protected by rubbergloves and eyes by protective goggles.

100 g. of l,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinoline-l-propionic acid hydrochloride are introduced withice-cooling into 1 l. of liquid anhydrous hydrofluoric acid in apolyethylene vessel equipped with a magnetic stirrer. The vessel is thensealed with a perforated screw cap and fitted with a Teflon orpolyethylene tube. The tube leads directly into the extractor shaft. Theapparatus is maintained for 2 days at 0 and for 3 days at then placed ina water-bath at about 30. Thereafter, the hydrofluoric acid is removedby evaporation while stirring with the magnetic stirrer.

The residue is poured onto a mixture of 500 g. of ice and l l. ofconcentrated ammonia cooled with an icecommon salt mixture. In so doing,the internal temperature should not exceed 30. The mixture is thenshaken out with eight 250 ml. portions of methylene chloride. Then, thecombined extracts are shaken out with two 200 ml. portions of water. Theaqueous phases are individually extracted with two 100 ml. portions ofmethylene chloride. All the methylene chloride phases are combined,dried over sodium sulfate, filtered and evaporated. There is obtained60-70 g. of residue which is dissolved in 300 ml. of absolute ether. Thesolution is treated with Carboraffm, filtered and concentrated toincipient crystallization. 1,2,3,8,9,9ahexahydro-5,6-dimethoxy-l-methyl-benzo[d,e ]quinolin-7-one is obtained in the form of colorlesscrystals. having a melting point of 8l-83. The substance i lightandheat-sensitive and is preferably stored in a refrigerator.

EXAMPLE 3 Preparation of l ,2,3,8,9,9a-hexahydro-5,6- dimethoxyl-methylbenzo[d,e ]quinolin-7-one 4.4 g. of concentrated sulfuric acid(about 96%) and 1.1 g. of fuming sulfuric acid (about 60% S0 are mixedat room temperature. 1.37 g. of l,2,3,4- tetrahydro-6,7-dimethoxy-2'methyl-isoquinoline-l-propionic acid ethyl ester are added with stirringto the obtained mixture. The resulting reaction mixture is heated to for5 minutes and subsequently poured onto g. of ice and 200 ml. of H 0. Theaqueous solution is made alkaline with 13 ml. of caustic soda (28%) andextracted with three 30 ml. portions of methylene chloride. The organicphase is dried over sodium sulfate and concentrated in a rotaryevaporator (pressure: 16 cm Hg, bath temperature 50). 0.4 g. of the oilyproduct are crystallized from ether. After filtering and air-drying,there are obtained 270 mg. of l,2,3,8,9,9ahexahydro-5,6-dimethoxyl-methyl-benzo [d,e]quinolin-7-one in the form of crystals having amelting point of 5962. After recrystallizing three times from ether, themelting point is at 715 74.

EXAMPLE 4 Preparation of l,2,3,8,9,9a-hexahydro-5,6- dimethoxyl-methylbenzo[ d ,e quinolin-7-one 50.0 g. of polyphosphoric acid areheated to 80, whereupon 5.0 g. of l,2,3,4-tetrahydro-6,7-dimethoxy-Z-methyl-isoquinoline-l-propionic acid hydrochloride are addedportionwise with stirring over a period of 3 minutes. The reactionmixture is heated to 80 for an additional 5 minutes and subsequentlypoured onto 500 ml. of H 0. The reaction vessel is rinsed with 100 ml.of ice water. The aqueous solution is made alkaline with caustic soda(28%) and extracted with three ml. portions of methylene chloride. Theorganic phase is dried over sodium sulfate and concentrated in a rotaryevaporator (pressure: 16 cm Hg, bath temperature: 50). 3.5 g. of theproduct are recrystallized from ether. After filtering and air-drying,l,2,3,8,9,9a hexahydro-5,6dimethoxyl -methyl-benzo[d,e ]quinolin-7-oneis obtained in the form of crystals having a melting point of 6870.After two recrystallizations, the melting point is 7375.

in Example 5, hereinafter set forth, there is described the conversionof l,2,3,8,9,9a-hexahydro-5 ,6- dimethoxy-l-methyl-benzo[d,e]quinolin-7-one to racemic nuciferoline. The remaining compounds offormula I or their salts can be converted into analogous alkaloids ofthe nuciferine type in a similar manner.

EXAMPLE 5 Preparation of racemic nuciferoline A solution containing 1.36g. of methyl ethynyl ketone in 20 ml. of benzene and a solutioncontaining 0.78 g. of potassium in 100 ml. of t-butanol aresimultaneously added dropwise to a solution containing 5.2 g. ofl,2,3.8,9,9a--hexahydro-5 ,6-dimethoxy- 1-methylbenzo[d,e]quinolin-7-one in 50 ml. of abosulte benzene which isstirred at 20 under a protective gas. After stirring for three hours,and additional 1.36 g. of methyl ethynyl ketone in 20 ml. of benzene areadded dropwise. The resulting mixture is stirred at 20 for a urther 16hours. Then, 1.2 g. of glacial acetic are ...1ded and the mixture isevaporated under reduced pressure. The residue is partitioned betweenwater and dilute aqueous ammonia (100 ml. each). The water phase isshaken out with four 50 ml. portions of methylene chloride. After dryingover sodium sulfate, the

3,896,132 5 6 combined organlc phases are evaporated under reclizing acompound of the formula duced pressure. The residue (7.l g.) ischromatographed with methylene chloride-methanol (98:2) on 350 g. ofKleselgel, 575 fractions each of 30 ml. are collected. Fractions 355-465contain 300 mg. of racemic R o i. N R

nuciteroline which melts at 225'-228 after crystalliza- H 3 tion fromethanol.

We claim: CH 1. A process for the preparation of a compound of 2 theformula i 10 I coon I! 4 a o N-R wherein R R, and R, are as previouslydescribed 0 and R is hydrogen or lower alkyl.

or a salt thereof, by treatment with sulfuric acid containing freesulfur trioxide at a temperature in the range wherein R R, and R, arelower alkyl. of about 65C. to about 85C.

or acid addition salts thereof, comprising the step of cy-

1. A PROCESS FOR THE PREPARATION OF A COMPOUND OF THE FORMULA